Adverse drug reactions (ADRs) continue to challenge healthcare systems worldwide, largely due to genetic differences in drug-metabolizing enzymes across populations. To address this, we conducted a comprehensive pharmacogenomic (PGx) survey of the South Korean (SKR) population, focusing on 21 clinically relevant pharmacogenes. Whole genome sequencing (WGS) was performed on 396 individuals, including healthy volunteers (n = 99), patients with chronic diseases (n = 95), and cancer patients with colon (n = 81), breast (n = 81), or gastric cancer (n = 40), aiming to establish genotype-informed drug dosing guidelines. High-throughput genotyping (HTG) of CYP2D6, along with comparisons to the 1,000 Genomes Project (1 KG) and the US National Marrow Donor Program (NMDP), revealed substantial variability in genes such as CYP2B6, CYP2C19, CYP4F2, NUDT15, and CYP2D6. For instance, intermediate metabolizer status for CYP2B6 was observed in 3.28% of SKR participants, resembling rates in Europeans (5.77%) and East Asians (5.36%), yet diverging significantly from other populations globally (p < 0.01). Nearly half of the SKR cohort (48.74%) were intermediate metabolizers for CYP2C19, with the *35 allele (2.02%) being uniquely present in SKR. The high-risk CYP4F2 *3 allele was considerably more prevalent in SKR (34.72%) compared to other East Asian groups (p < 0.01). NUDT15 poor metabolizers were identified in 0.76% of SKR individuals, similar to other East Asian populations (1.59%), whereas TPMT poor metabolizers were rare, mainly found in Europeans and Africans, with a single case in SKR. Notable differences were also detected in CYP2D6 variants rs1065852 and rs1135840.Among 72 drugs evaluated, the vast majority of patients (93.43%, n = 370) required at least one dosage adjustment, averaging 4.5 medications per individual, and 31.31% (n = 124) needed adjustments for more than five drugs. These findings underscore the high degree of pharmacogenetic diversity in SKR and highlight the critical importance of integrating population-specific PGx information into clinical practice to improve drug safety and therapeutic outcomes. This extensive profiling lays the groundwork for precision medicine in South Korea and offers insights with potential global relevance.
